Activated iNKT cells control CNS autoimmunity in a mechanism that involves MDSCs

Background:   Invariant NKT (iNKT) cells are a subset of T lymphocytes that recognize glycolipid antigens presented by the MHC class I-related protein CD1d. Activation of iNKT cells with glycolipid antigens such as the marine sponge-derived reagent alpha-galactosylceramide (a-GalCer) results in the rapid production of a variety of cytokines and activation of many other immune cell types. These immunomodulatory properties of iNKT cells have been exploited for the development of immunotherapies against a variety of autoimmune and inflammatory diseases but mechanisms by which activated iNKT cells confer disease protection have remained incompletely understood. Here, we hypothesize that CD11b⁺Gr1⁺ myeloid-derived suppressor cells (MDSCs) activated by iNKT cells play an important role in controlling pathogenic T cells generated during EAE. 

Objectives: To understand how iNKT cells and myeloid-derived suppressor cells (MDSCs) cooperate in preventing autoimmunity of the central nervous system (CNS). 

Methods: Development of experimental autoimmune encephalomyelitis (EAE) in B6 mice, its prevention by activated iNKT cells and functional characterization of MDSCs. 

Results:   Activation of iNKT cells using a-GalCer induced the expansion and acquisition of an M2-like phenotype in MDSCs with superior immunosuppressive activities in the spleen of mice induced for the development of EAE. Disease protection in these animals also correlated with recruitment of MDSCs to the central nervous system. Depletion of MDSCs abrogated the protective effects of a-GalCer against EAE and, conversely, adoptive transfer of MDSCs from a-GalCer-treated mice ameliorated passive EAE induced in recipient animals. These properties of MDSCs involved expression of inducible nitric oxide synthase, arginase-1 and IL-10. 

Conclusions: Our findings have revealed cooperative immunosuppressive interactions between iNKT cells and MDSCs that might be exploited for the development of improved immunotherapies for MS and other autoimmune and inflammatory diseases.